Hubs and spokes of the lateral hypothalamus: cell types, circuits and behaviour

The hypothalamus is one of the most phylogenetically conserved regions in the vertebrate brain, reflecting its critical role in maintaining physiological and behavioural homeostasis. By integrating signals arising from both external and internal homeostatic challenges, it governs a litany of behaviourally important functions essential for survival. In particular, the lateral hypothalamic area (LHA) is central to the orchestration of sleep-wake states, feeding, energy balance and motivated behaviour. Underlying these diverse functions is a heterogeneous assembly of cell populations typically defined by neurochemical markers, such as the well-described neuropeptides hypocretin/orexin (Hcrt/Ox) and melanin-concentrating hormone (MCH). However, anatomical and functional evidence suggests a rich diversity of other cell populations with complex neurochemical profiles that include neuropeptides, receptors and components of fast amino acid neurotransmission. Collectively, the LHA acts as a hub for the integration of diverse central and peripheral signals and, through complex local and long-range output circuits, serve to coordinate adaptive behavioural responses to the environment. Despite tremendous progress in our understanding of the LHA, defining the identity of functionally discrete LHA cell types, how they are organized into specific neural circuits and how they regulate complex behaviour remain significant challenges in the field. The recent application of powerful new techniques, such as optogenetics, chemogenetics and in vivo electrophysiology and imaging in awake and behaving animals, has renewed interest in the nature of LHA cell types and circuits. In this review, we address the neurochemical and cellular heterogeneity of LHA neurons and circuits and its role in a vast array of behaviours. From pioneering findings to recent developments, we review how the interrogation of LHA function is rapidly accelerating progress towards a mechanistic understanding of how the LHA coordinates complex behaviours such as feeding, reward, motivated behaviour, sleep, wakefulness, stress and anxiety.

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